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  • Dysregulation of catecholaminergic neurotransmission particu


    Dysregulation of catecholaminergic neurotransmission, particularly the dopaminergic system, has long been correlated with the development of neuroinflammation and HAND. Studies specifically examining role of catecholamines in HIV pathogenesis, particularly focused on NeuroHIV, are relatively few. However, over the course of the epidemic, researchers found that infected individuals show a number of catecholaminergic changes. These include increased damage in dopaminergic regions of the CNS, altered autonomic nerve activity, changes in catecholamine metabolism, stress induced changes in infection and response to cART, and altered viral GSK2118436 and dysregulated immune responses resulting from changes to catecholaminergic tone (Gelman, 2012, Reyes, 1991, Aylward, 1993, Hestad, 1993, Berger, 1994, Fujimura, 1997, Berger and Arendt, 2000, Itoh et al., 2000, Czub, 2001, Czub, 2004, Gelman, 2006, Anthony and Bell, 2008, Agrawal, 2010, Ferris, 2010, Fitting et al., 2015, Gaskill, et al., 2017, Kumar, 1991, Kumar, 2002, Kumar, 2003, Kumar, 2009, Koutsilieri, 1997, Koutsilieri, 2002, Cole, 2001, Cole, 2008, Gaskill, 2013, Sloan, 2006). Further, data show that catecholamines, particularly dopamine and norepinephrine, are important mediators for neuroimmune crosstalk (Gaskill, 2013, Flierl, 2008, Cole et al., 1999, Farber et al., 2005, Gaskill, 2012, Sarkar, 2010). As the dysregulated immune response is central to the etiology of NeuroHIV, these data suggest that disruptions in catecholaminergic tone in response to HIV infection, drug abuse, stress or specific therapeutic drugs, could exacerbate HIV neuropathogenesis. The dearth of studies in this area, particularly those dissecting the mechanisms by which catecholamines mediate their effects on NeuroHIV, has hindered our ability to understand and effectively treat these components of HIV neuropathogenesis. Therefore, this review will discuss what is known about the role of catecholamines in the development of NeuroHIV. We briefly discuss the state of CNS infection in the cART era, touching on the specific effects in dopaminergic and adrenergic systems, and then discuss catecholamine biology and what is known about the catecholaminergic systems in immune cells. We will then focus on catecholaminergic modulation of HIV infection and neuroinflammatory processes, and how these effects might enhance the development of NeuroHIV. The neurologic complications of HIV are a growing problem within the infected population, making the development of new neuroprotective strategies a pressing medical need. This review will contribute to a better understanding of the bidirectional interactions between catecholamines and HIV infection of the CNS, leading to novel therapeutic targets for the treatment of NeuroHIV.
    HIV neuropathogenesis in the cART era Prior to the widespread use of cART, HIV infection of the CNS commonly resulted in significant neuropathology including HIV encephalitis (HIVE), meningitis, microglial nodules, multinucleated giant cells, reactive gliosis, and neuronal injury and death (Navia, 1986, Anthony and Bell, 2008, Everall et al., 2005, Bell, 1998). Severe neurocognitive impairment was also common, with HIV-associated dementia (HAD) found in 15–20% of infected individuals. Significant neuropathology was often coincident with neurocognitive impairment in many infected individuals, but the relationship between neurological damage and cognitive impairment is not entirely causal. Studies demonstrated that HIVE did not explain all HIV-associated dementia, and the best correlate for the development of HIV-associated neuropathology was myeloid cell activation in the CNS (Burdo et al., 2013, Anthony and Bell, 2008, Glass, 1995). With cART, HIVE and HAD are almost nonexistent, and severe forms of neurocognitive impairment are rare, but the prevalence of mild and asymptomatic forms of neurocognitive impairment have increased, and HAND is still found in 40 – 70% of HIV infected individuals (Saylor, 2016, Heaton, 2010, Cysique et al., 2004, Clifford, 2017, van den Dries, 2017). Despite suppression of HIV replication below the limit of detection, fully suppressed individuals still show signs of NeuroHIV, and data show no correlation between neuropathology, neurocognitive impairment, and CNS viral load (Gelman, 2013, Clifford, 2017, van den Dries, 2017, McArthur, 2004, Sanford, et al., 2017, Baker, 2015, Underwood, 2017). This indicates that the development of HIV-associated neurological disease does not derive solely from damage associated with actively replicating virus (Sevigny, 2004, McArthur, 2004, Tavazzi, 2014).